Prevention Opportunities for Oral Contraceptive-Associated Ischemic Stroke

Abstract

Background and Purpose

Literature suggests a small increased risk of ischemic stroke with oral contraception (OC) use. We evaluated the association of stroke and OC-use in women on the basis of whether they recalled being advised by a physician not to use OC or to discontinue OC-use due to presence of stroke risk-modifiers, and whether such advice resulted in behavioral change.

Methods

572 women (224 strokes;348 controls) aged 15–49 were interviewed about OC-use and risk-modifiers including cigarette-smoking and headaches, among others.

Results

The adjusted odds ratio for OC-use and stroke was 2.00 (95%CI=1.29–3.09). The association of OC-use with stroke was stronger in women that reported receiving doctor’s advice against OC-use due to presence of other stroke risk-modifiers (OR=3.12;95%CI=1.62–6.00) than in women who did not recall receiving such advice (OR=1.31;95%CI=0.71–2.43). Of 256 women who recalled being advised by their doctor not to start OC or to discontinue OC-use due to the presence of other stroke risk-modifiers, 24% were still on OC at the time of stroke or interview.

Conclusions

We confirm that certain medical conditions increase the risk of stroke during OC-use, and demonstrate the importance of physician counseling in those using OC in the setting of concurrent high risk conditions and the need for improved patient compliance with such counseling.

Introduction

Oral contraception (OC) has been associated with an increased risk of ischemic stroke [1]. We sought to determine if the elevated stroke risk in women using OC was restricted to women with other concurrent conditions (risk-modifiers); whether women with these conditions recalled being advised by their physician not to begin using OC or to stop using OC, and; whether this advice resulted in behavioral change.

Material and Methods

Study Population

The Stroke-Prevention-in-Young-Women-Study is a population-based case-control study consisting of 514 cases aged 15–49 at the time of stroke and 617 controls matched by age, region of residence, and ethnicity; details of study design have been previously published [2]. Exclusions included missing data on OC-use (n=17); unknown menstrual status (n=3); postmenopausal or currently pregnant, pregnant within last 2 months or currently nursing (n=283), prior surgery to remove the uterus, ovaries, both, or a tubal ligation (n=256), resulting in a final study cohort of 224 cases and 348 controls.

Demographic variables, OC-use, and presence of stroke risk-modifiers were determined through a standardized face-to-face interview. Current OC-use was defined as use within 1 month before the stroke with a comparable reference time for matched-controls. Participants were asked if they had been told by a physician not to start OC or to discontinue OC-use due to any of the following conditions: cigarette-smoking, headaches, high-blood-pressure, diabetes-mellitus, sickle-cell-disease or -trait, prior TIA, chest-pain or myocardial-infarction, blood clots in legs or lungs, or a family history of heart problems.

Analysis

Cases and controls were compared using t-tests for continuous variables and Mantel-Haenszel chi-square tests for categorical variables (SAS:Version-9.2). Unadjusted-associations between ischemic stroke and risk-modifiers were then examined within pre-defined subgroups using chi-square or Fisher-exact tests. We additionally categorized subjects according to whether they had received physician advice not to start using OC or to discontinue OC-use due to the presence of one or more risk-modifiers versus those who had not received such advice. We estimated the association between stroke and OC-use in those receiving physician advice against OC-use versus those who did not receive such advice using logistic-regression adjusting for age and ethnicity (self-report). Two-tailed p-values <.05 were considered statistically significant.

Results

Table 1 demonstrates participant characteristics. There was no statistically significant difference between the percentages of cases and controls that were told not to start or to stop OCs due to the following risk conditions: current-smoking, headache, hypertension, chest-pain or myocardial-infarction, or history of blood clots in the legs or lungs. Due to the paucity of participants with diabetes-mellitus, sickle-cell-disease or -trait, TIA, and family history of heart problems, these variables were excluded from further analyses.

Table 1.

Participant characteristics.

	Cases (n=224)	Controls (n=348)	P-value
Mean-age±SD	36.4±8.2	34.7±8.4	0.02
Self-Reported Race (%)
European-ancestry	51.8	65.5
African-ancestry	42.0	29.6	0.005
Other	6.2	4.9
Stroke Risk-modifiers*
Current Smoker (%)	20.5	17.2	0.32
Headache (%)	16.1	13.8	0.45
Hypertension (%)	5.4	5.5	0.96
Chest-Pain or Myocardial-Infarction (%)	1.3	1.7	0.72
History of blood clots in the legs or lungs (%)	1.8	2.3	0.68

^*Risk-modifier percentages based upon whether participants were told by doctor to not start or to discontinue OC-use based on each risk-modifier.

Evaluating the entire population, OC-use was significantly associated with stroke (adjusted-OR=2.00;95% CI=1.29–3.09) as indicated in Table 2. Table 2 further demonstrates the association of OC-use with stroke stratified by the absence or presence of doctor’s advice against OC-use due to the presence of one or more risk-modifiers. OC-use was highly associated with stroke in women receiving physician advice not to use OC due to the presence of risk-modifiers (OR=3.12;95%CI=1.62–6.00), although the association was substantially attenuated and no longer statistically-significant in women who did not receive such advice. (OR=1.31;95%CI=0.71–2.43). When we considered individual conditions that resulted in physician advice against OC-use, the two most common reasons for receiving such advice were current-smoking (106 of 256;42%) and headaches (84 of 256;33%). When stratified by these individual conditions, OC-use was strongly associated with stroke among current smokers (OR=4.29;95%CI=1.51–12.16), but much less so among women who did not currently smoke (OR=1.70;95%CI=1.04–2.79). Similarly, OC-use was strongly associated with stroke in women reporting headaches (OR=3.82;95%CI=1.27–11.56), but only borderline significant in women reporting they were headache free (OR=1.63;95%CI=1.01–2.66). Stratified analyses evaluating OC-use associated stroke risk in the presence or absence of hypertension, chest-pain or myocardial-infarction, or a history of blood clots in the legs or lungs, demonstrated no significant associations (results not shown). Among women who received physician advice against OC-use (either not to start or to discontinue), 34% of cases and 18% of controls were still on OC at the time of stroke or interview, respectively (p=0.03).

Table 2.

OC-use and stroke risk.

	Case (N=224)	Control (N=348)	OR;95%CI;p-value
Entire population  Used OC=yes/no	57/167	63/285	2.00;1.29–3.09;0.002
Had >= 1 Risk-modifier*	N=99	N=157
Used OC=yes/no	34/65	28/129	3.12;1.62–6.00;0.001
Had No Risk-modifiers*	N=125	N=191
Used OC=yes/no	23/102	35/156	1.31;0.71–2.43;0.38
Current Smokers	N=46	N=60
Used OC=yes/no	17/29	12/48	4.29;1.51–12.16;0.006
Non-Smokers	N=178	N=288
Used OC=yes/no	40/138	51/237	1.70;1.04–2.79;0.04
Had Headaches	N=36	N=48
Used OC=yes/no	17/19	11/37	3.82;1.27–11.56;0.02
No Headaches	N=188	N=300
Used OC=yes/no	40/148	52/248	1.63;1.01–2.66;0.05

^*Includes current smoking, headache, hypertension, history of chest-pain or myocardial-infarction, and/or history of blood clots in the legs or lungs

Physician advice (not to start or discontinue OC) and patient compliance

There were 256 women with ≥1 risk-modifiers (99 cases;157 controls). Among these women, only 38 (15%) recalled being advised not to start OC on the basis of their pre-existing risk-modifier profile; a similar percentage of cases (13%) and controls (16%) recalled such physician counseling. Of note, 9 (24%) of these 38 women were taking OC at the time of stroke or interview despite being advised not to start OC.

Of the 256 women with ≥1 risk-modifiers, 93 (36%) recalled being told to discontinue OC (40 cases;53 controls) on the basis of their risk-modifier profile. A similar percentage of cases (40%) and controls (34%) recalled such physician counseling. Of note, 14 (15%) of the 93 were taking OC at the time of stroke or interview despite being told to discontinue OC-use.

Discussion

Several conditions, termed risk-modifiers, have been shown to increase stroke risk in the setting of OC-use, with smoking [3] and headache [4] being those most cited. We confirm these findings demonstrating a significantly increased risk of stroke in the setting of OC-use in those with one or more concomitant risk-modifiers (OR=3.12;95%CI=1.62–6.00), but no significantly increased risk in those free of such conditions (OR=1.31;95%CI=0.71–2.43). In further agreement with the existing literature, those at highest risk were current smokers (OR=4.29;95%CI=1.51–12.16) and those with headaches (OR=3.82;95%CI=1.27–11.56). Combinations of these risk-modifying conditions in the setting of OC-use have also been shown to act synergistically, thereby elevating risk in a greater-than additive fashion. Of these, the combination of smoking and migraine headache in the setting of concurrent OC-use has been demonstrated to be particularly deleterious [5]. While our sample size precluded a detailed evaluation of this combination, interestingly, of the 22 study participants that were smokers with headaches, 8 of the 13 cases were on OC, but none of the 9 control subjects were so. As such, our data appears to agree with a markedly elevated risk of stroke in this setting [5].

Our study not only acts to confirm previously recognized high risk subgroups, but also evaluates if patients with such conditions recalled being told by a physician not start or to stop OC as based on the existence of these conditions, and whether they did so or not. Currently there exists scant literature regarding the physician-patient encounter in this topic area, thereby making our study unique. As described in the Results, evaluation of our pre-stroke physician counseling data demonstrated that only ~15% (38/256) of patients recalled being told not to start OC on the basis of their risk-modifier profile. However, once patients were taking OC physician counseling improved, with ~36% (93/256) of the participants with 1 or more high risk conditions being told to discontinue OC-use. Further, we also found that patients were not optimally compliant with physician instructions when they were provided, with 24% (9/38) of the women with 1 or more high risk conditions that were advised not to start OC remaining on OC at the time of their stroke or interview. These results indicate that in the setting of OC-use and concomitant risk-modifiers, improved physician counseling as well as improved patient compliance could potentially reduce ischemic stroke rates.

Our study benefited from the rigorous exclusion criteria designed to limit the confounding effects of hormonal fluctuations associated with pregnancy, the post-partum-period, and lactation. Unfortunately these same criteria also acted to reduce our sample-size, thereby limiting our ability to evaluate the risk-modifiers by stroke subtype; headache type (non-migraine vs. migraine+/−aura), OC by formulation (estrogen vs. progestin vs. combination), OC dose, and OC delivery-method. Our sample-size also limited our ability to control for other vascular risk factors (e.g.: diabetes, thrombophilia), which potentially may have produced unmeasured confounding. Further, our data was collected retrospectively; as such, our results could be influenced by recall bias, particularly in the sense that those who suffered a stroke might be more likely to remember whether they did or did not receive specific-physician instructions relating to OC-use. Lastly, there is a chance that subjects may have misunderstood or incorrectly answered our questions.

Conclusion

We confirm that certain medical conditions increase the risk of stroke during OC-use, and demonstrate the importance of physician counseling in those using OC in the setting of concurrent high risk conditions and the need for improved patient compliance with such counseling.